Novel compounds advantageous in the treatment of central nervous system diseases and disorders

ABSTRACT

A series of novel compounds showing anticonvulsant activity is described. Such pharmaceutically active compounds may also show utility in the treatment of other central nervous system (“CNS”) diseases and disorders, such as anxiety, depression, insomnia, migraine headaches, schizophrenia, Parkinson&#39;s disease, spasticity, Alzheimer&#39;s disease, and bipolar disorder. Furthermore, such compounds may additionally find utility as analgesics (e.g., for the treatment of chronic or neuropathic pain) and as neuroprotective agents useful in the treatment of stroke(s), chronic neurodegenerative diseases (such as Alzheimer&#39;s disease and Huntington&#39;s disease), and/or traumatic brain and/or spinal cord injuries. Moreover, these/such compounds may also be useful in the treatment of status epilepticus and/or as chemical countermeasures.

RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional PatentApplication Ser. No. 61/037,987 filed 19 Mar. 2008 and entitled “NOVELCOMPOUNDS ADVANTAGEOUS IN THE TREATMENT OF CENTRAL NERVOUS SYSTEMDISEASES AND DISORDERS,” the entirety of which is incorporated herein byspecific reference.

BACKGROUND OF THE INVENTION

1. The Field of the Invention

The present invention relates to novel compounds showing activity in thecentral nervous systems (CNS) of experimental animals. Morespecifically, the present invention relates to novel compounds withanticonvulsant activity that exhibit increased/improved toxicologicalsafety (i.e., decreased toxicity), increased/improved metabolicstability, longer half-life, and/or a superior side effect profile,while producing similar or increased biological activity (i.e.,efficacy), when compared to currently available CNS therapeutic agents.

2. The Related Technology

A number of pathological conditions (e.g., epilepsy, stroke, bipolaraffective disorder, migraine headaches, anxiety, depression, insomnia,schizophrenia, chronic or neuropathic pain, spasticity, spinal cordinjury, and chronic neurodegenerative disorders), and diseases (e.g.,Parkinson's disease, Huntington's disease, and Alzheimer's disease) arecharacterized by abnormalities in the normal function of the centralnervous system (CNS). These conditions and diseases typically respond topharmacologic intervention with compounds or substances that modulateCNS activity. Compounds with this activity include the compounds of thepresent invention, which are herein disclosed to treat abnormalities ofthe CNS, such as epilepsy. While currently available therapeutants oftenhave good CNS activity, they frequently exhibit other undesirableproperties, such as chronic toxicity, severe and/or unpleasant sideeffects, and inadequate pharmacokinetic properties, such as a shortpharmacologic half-life. For example, a short half-life in a CNStherapeutant may require its frequent administration in order to sustaintherapeutic concentrations of the drug without eliciting adverseeffects, and where frequent dosing schedules are required, the cost oftherapy may increase. In addition, as the required dosing frequencyincreases, patient compliance tends to decrease. It would therefore bedesirable to provide additional compounds that modulate CNS activity andhave improved properties, such as, e.g., an increased half-life,increased activity (i.e., improved efficacy), and/or increased metabolicstability (e.g., fewer toxic metabolites) when compared to those ofcurrently available therapies. Furthermore, improved andsimpler/simplified synthetic and chemical manufacturing processes can bedeveloped which can help to make the useful compounds of the inventionmore widely available to a larger portion of the patient population.

Related art may be found in U.S. Pat. No. 5,463,125 (Sandoval et al.,“Phenyl alcohol amides having anticonvulsant activity”), WO9941229[Carvajal Sandoval et al., “Halogenated phenyl alcohol amides (ligandsof GABAB receptor) having an anticonvulsant activity”], WO03091201(Carvajal Sandoval et al., “DL-Hydroxy-alkyl-phenylamides havinganticonvulsive activity”), WO2005085182 (Meza Toledo,“DL-Hydroxybenzamides having anticonvulsive activity”), and U.S. PatentApplication 20060287397 (Meza Toledo, “Dl-Hydroxy-alkyl-phenylamideshaving anticonvulsive activity”). An important distinction between theart cited above and that of the present invention is that the cited artcontains and refers to compounds which are structurally related togamma-hydroxybutyric acid (gamma-hydroxybutyrate, or GHB), whereas thecompounds of the present invention are structurally related to3-methylbutyramide.

BRIEF SUMMARY

A series of novel amides with anticonvulsant activity are hereindisclosed, many of which have a phenyl group attached to the amidemoiety via a short and variously branched/substituted aliphatic linker.Other compounds of the invention (as shown below) are amides which arederivatives of optically active amino acids (e.g., D or L), such asalanine (Z═CH₃, below), valine [Z═CH(CH₃)₂], leucine [Z═CH₂CH(CH₃)₂],isoleucine [Z═CH(CH₃)CH₂CH₃], or phenylalanine (Z═CH₂C₆H₅), or theoptically inactive amino acids, glycine (Z═H) or taurine [R₂═(CH₂)₂SO₃H,below]. Such compounds are exemplified by the following formulas:

A CNS-active compound having the Formula I:

In Formula I, Ar can be an optionally substituted phenyl, optionallysubstituted naphthyl, optionally substituted tetrahydronaphthyl,optionally substituted indane, or an optionally substituted heterocyclicaryl, wherein up to 5 substituents may be present. Each substituent onAr can be independently selected from the group consisting of alkyl,cycloalkyl, halogen, alkoxy, thioalkyl, sulfoxyalkyl, sulfonylalkyl,alkylene dioxy, haloalkyl, haloalkoxy, OH, CH₂OH, CONH₂, CN, acetoxy,N(alkyl)₂, benzyl, benzyloxy, α,α-dimethylbenzyl, NO₂, CHO, CH₃CH(OH),acetyl, OCH₂COOH, and combinations thereof. Also, the Ar can include anoptionally substituted aromatic ring system attached to one or two atomsof the Ar, such aromatic rings being selected from the group consistingof phenyl, phenoxy, heterocyclic aryl, and combinations thereof. The Arand/or substituent thereon can have up to 5 substituents, and eachsubstituent can be independently selected from the group consisting ofalkyl, cycloalkyl, halogen, alkoxy, thioalkyl, sulfoxyalkyl,sulfonylalkyl, alkylene dioxy, haloalkyl, haloalkoxy, OH, CH₂OH, CONH₂,CN, acetoxy, N(alkyl)₂, NO₂, CHO, CH₃CH(OH), acetyl, and OCH₂COOH.Optionally, the Ar and/or aromatic rings can include bifunctionalsubstituents that form a ring with the Ar and/or aromatic rings, whereinthe bifunctional substituents are an optionally substituted alkyl,cylcoalkyl, methylenedioxy, ethylenedioxy, or other alkylenedioxy, andcombinations thereof.

In Formula I, R₁ and R₂ can each be independently at least one of, H,long or short chain substituted or unsubstituted alkyl, substituted orunsubstituted cycloalkyl, CW₂phenyl. Each W is independently selectedfrom the group consisting of H, methyl and ethyl (except that both Wscannot be ethyl). Up to 5 substituents may be present in the phenylgroup, and each substituent is independently selected from the groupconsisting of halogen, alkoxy, thioalkyl, sulfoxyalkyl, sulfonylalkyl,haloalkyl, haloalkoxy, CONH₂, CN, acetoxy, N(alkyl)₂, NO₂, and acetyl.

In another embodiment, R₁ is H and R₂ is (CH₂)₂SO₃H, or CHZCOOH, whereinZ is one of the group consisting of H, CH₃, CH(CH₃)₂, CH₂C₆H₅,CH₂CH(CH₃)₂, and CH(CH₃)CH₂CH₃. Optionally, R₁ and R₂ together arecycloalkyl.

In Formula I, R₃ is either hydroxy, substituted or unsubstituted alkyl,substituted or unsubstituted cycloalkyl, or together with R₄ cycloalkyl.Optionally, if R₃ is OH, then R₄ is not an ethyl.

In Formula I, R₄ is one of a substituted or unsubstituted alkyl,substituted or unsubstituted cycloalkyl, or together with R₃ cycloalkyl.

In Formula I, X is one of nothing, substituted or unsubstitutedalkylene, methylene, ketone, CHOH, oxygen, NR₁, sulfur, sulfone, orsulfoxide.

A CNS-active compound having Formula II:

In Formula II, R₁ and R₂ are each independently at least one of H, longor short chain substituted or unsubstituted alkyl, substituted orunsubstituted, cycloalkyl, CW₂phenyl, or combinations thereof. W isindependently selected from the group consisting of H, methyl and ethyl,except that both Ws cannot be ethyl. Up to 5 substituents may be presentin the phenyl group or cylcoalkyl group, and each substituent isindependently selected from the group consisting of halogen, alkoxy,thioalkyl, sulfoxyalkyl, sulfonylalkyl, haloalkyl, haloalkoxy, CONH₂,CN, acetoxy, N(alkyl)₂, NO₂, and acetyl. Optionally, R₁ is H and R₂ is(CH₂)₂SO₃H, or CHZCOOH, wherein Z is one of the group consisting of H,CH₃, CH(CH₃)₂, CH₂C₆H₅, CH₂CH(CH₃)₂, and CH(CH₃)CH₂CH₃. In anotheroption, or R₁ and R₂ together are cycloalkyl.

R₄ and R₅ are each independently either optionally substituted phenyl oroptionally substituted heterocyclic aryl, wherein up to 5 substituentsmay be present and each substituent is independently selected from thegroup consisting of halogen, alkoxy, thioalkyl, sulfoxyalkyl,sulfonylalkyl, haloalkyl, haloalkoxy, CH₂OH, CONH₂, CN, acetoxy,N(alkyl)₂, NO₂, acetyl, and OCH₂COOH.

Y is either nothing, substituted or unsubstituted methylene, or othersubstituted or unsubstituted alkylene.

In one embodiment, the present invention includes a CNS-active compoundhaving one of the following formulas:

In one embodiment, R₁ and R₂ are each independently at least one of H,long or short chain substituted or unsubstituted alkyl, substituted orunsubstituted, cycloalkyl, CW₂phenyl, or combinations thereof. W isindependently selected from the group consisting of H, methyl and ethyl,except that both Ws cannot be ethyl. Up to 5 substituents may be presentin the phenyl group or cylcoalkyl group, and each substituent isindependently selected from the group consisting of halogen, alkoxy,thioalkyl, sulfoxyalkyl, sulfonylalkyl, haloalkyl, haloalkoxy, CONH₂,CN, acetoxy, N(alkyl)₂, NO₂, and acetyl. Optionally, R₁ is H and R₂ is(CH₂)₂SO₃H, or CHZCOOH, wherein Z is one of the group consisting of: H,CH₃, CH(CH₃)₂, CH₂C₆H₅, CH₂CH(CH₃)₂, and CH(CH₃)CH₂CH₃. In anotheroption, R₁ and R₂ together are cycloalkyl.

In one embodiment, R₁ is H and R₂ is (CH₂)₂SO₃H, or CHZCOOH, wherein Zis one of the group consisting of: H, CH₃, CH(CH₃)₂, CH₂C₆H₅,CH₂CH(CH₃)₂, and CH(CH₃)CH₂CH₃. Optionally, R₁ and R₂ together arecycloalkyl.

In one embodiment, R₃ is either hydroxy, substituted or unsubstitutedalkyl, substituted or unsubstituted cycloalkyl, or together with R₄cycloalkyl. Optionally, if R₃ is OH, then R₄ is not an ethyl.

In one embodiment, R₄ is one of a substituted or unsubstituted alkyl,substituted or unsubstituted cycloalkyl, or together with R₃ cycloalkyl.

In one embodiment, R₅ is one of H, Cl, F, CF₃, CN, C₁₀₅ alkyl, C₁₀₅alkoxy, OCF₃, CONR₁R₂, halogen-substituted alkyl, halogen-substitutedalkoxy,

In one embodiment, X is one of nothing, substituted or unsubstitutedalkylene, methylene, ketone, CHOH, oxygen, NR₁, sulfur, sulfone, orsulfoxide.

In one embodiment, n can be from 0-5, more preferably from 1-3, and mostpreferably from 1 to 2.

In one embodiment, any of Formulas I-8 can be characterized as follows:R₁ is one of H, CH₃, (CH₂)₂SO₃H, or CHZCOOH, wherein Z is one of thegroup consisting of: H, CH₃, CH(CH₃)₂, CH₂C₆H₅, CH₂CH(CH₃)₂, andCH(CH₃)CH₂CH₃, combination thereof, or derivative thereof; R₂, R₃, andR₄ are independently one of H, CH₃, substituted or unsubstituted alkyl,OH, OCH₃, substituted or unsubstituted alkoxy, combination thereof, orderivative thereof; R₅ is one of H, Cl, F, CF₃, CN, C₁₀₅ substituted orunsubstituted alkyl, C1-C5 substituted or unsubstituted alkoxy, OCF₃CONR₁R₂, combination thereof, and derivative thereof; n=1-5, preferably1-3; and X═O, NR₁, nothing, C═O, S, SO₂, combination thereof, andderivative thereof.

These and other embodiments and features of the present invention willbecome more fully apparent from the following description and appendedclaims, or may be learned by the practice of the invention as set forthhereinafter.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the chemical structures of the novel compounds of theinvention that are pharmacologically active in the central nervoussystems (CNS) of (for example) mammals, and which exemplify embodimentsof the present invention.

FIG. 2 shows the relative biological activity of the compounds of theinvention, specifically showing those compounds which are preferred(second category, ED₅₀<300 mg/kg) and most preferred (first category,ED₅₀<100 mg/kg).

FIG. 3A shows the structures of further compounds of the invention whichare also in the category of most preferred compounds.

FIG. 3B shows the structures of further compounds of the invention whichare also in the category of most preferred compounds.

FIGS. 4A-40 illustrate examples of the syntheses of various compoundsand key intermediates.

DESCRIPTION OF THE ILLUSTRATED EMBODIMENTS 1. Overview

The inventors have discovered that the compounds of the invention andcertain of their pharmacologically active analogs and congeners can beadministered in vivo to effect a modulation of CNS activity. That is,these agents modulate CNS activity, by enhancing inhibitory, ordecreasing excitatory, neurotransmission centrally, without completesuppression of all activity. Pursuant to the present invention,therefore, a subject who receives such an agent is not overtly sedated,anesthetized, or paralyzed in the context of, for example, decreasingseizures (no anesthesia), decreasing muscle tone (no paralysis),eliciting a calmative effect (no sedation), or ameliorating anambulatory syndrome such as spasticity (no weakness or flaccidity).

A number of pathologies, exemplified by convulsions (seizures),spasticity, affective mood disorders, such as bipolar mood disorder,headaches (chronic, cluster, migraine), restlessness syndromes,neuropathic pain, and movement disorders, have at least one symptom thatis alleviated by a modulation of CNS activity. Accordingly, anindividual who suffers from such a pathology is a candidate for therapythat entails, pursuant to the present invention, the individualsreceiving a pharmaceutical formulation or composition containing thecompounds of the invention or one of their structurally related analogsor congeners as one of the principal active ingredients.

2. Exemplary Pathologies Ameliorated by a Modulation of Central NervousSystem (CNS) Activity

CONVULSIONS: Epilepsy is a common disorder which has many causes, and itcan be very difficult to control clinically, often requiring treatmentfor many years to keep seizures under control. Researchers have statedthat “[a]t this time, there is no satisfactory treatment for epilepsy ina substantial proportion of patients. Clinical trials have shown thatcertain patients have a better response to one drug than another, evenwhen the patients have similar types of seizures and the drugs havesimilar mechanisms of action. The frequency and severity of side effectsalso varies substantially. Thus, multiple medications with differentmechanisms of action and attendant side effects will be needed fortreatment of epilepsy until either epilepsy can be cured or a potent,safe new drug with broad activity is discovered” and developed. Dichteret al., Drug Therapy 334:1583 (1996).

Due to the widespread availability of reasonably predictive andexperimentally accessible animal models of convulsant states, a numberof clinically useful anticonvulsants have been prepared and developed.For example, see Cereghino et al., “Introduction,” in ANTIEPILEPTICDRUGS, 4th ed., pages 1-11 (Rave Press 1995), which states: “In manypatients, seizures can be controlled with currently availableantiepileptic drugs, but 25 to 30 percent of patients continue to haveseizures despite optimal therapy, while many others experienceunacceptable side effects.” Dichter et al. (1996) supra.

Thus, many anticonvulsants in clinical use are plagued by the occurrenceof significant side effects, including troublesome daytime sedation,muscular weakness, tolerance, gingival hyperplasia, and potentiallyfatal blood dyscrasias and hepatotoxicity. Many of these side effectsare especially of concern in the clinical management (treatment) ofepilepsy in children.

The present invention can be used to treat convulsive disorders such asepilepsy. That is, the compositions and pharmaceutical formulations andcompositions of the invention display “anticonvulsant activity,” whichis evidenced by a reduction of the severity, number, or duration ofconvulsions in animal models of epilepsy. To alleviate convulsionsincludes reducing the severity, number of duration of convulsions in apatient. Accordingly, the novel compositions and pharmaceuticalformulations and compositions should be useful in treating conditionssuch as, but not limited to, generalized tonic-clonic seizures, absenceseizures, myoclonic seizures, simple partial seizures, complex partialseizures, secondarily generalized partial seizures, status epilepticus,and trauma-induced seizures, as occur following head injury or surgery.

SPASTICITY: Spasticity is a disorder characterized by an increase intonic stretch reflexes (muscle tone) with exaggerated tendon jerksresulting from hyperexcitability of the stretch reflex. Lance, Symposiasynopsis, in SPASTICITY—DISORDERED MOTOR CONTROL, Feldman et al. (Eds.)(1980). Major disease states and conditions associated with spasticityinclude multiple sclerosis, cerebral palsy, stroke, trauma or injury tothe spinal cord, and head trauma. Symptoms that occur with spasticityinclude painful flexor and extensor spasms, increased or exaggerateddeep-tendon reflexes, clonus, muscular weakness, fatigue, lack ofdexterity, various degrees of loss of general motor function, paralysis,and impairment of sleep.

The pathological states observed in spasticity are fundamentallydifferent at the physiological level from the commonly experienced acutemuscular aches, strains, and sprains that occur from a localizedexternal insult to a particular muscle, i.e., outside of or peripheralto the CNS. These pathological states also are different from therelatively common involuntary spasms or smooth muscle, such as vascularspasms, bladder spasms, and bronchial spasms. Such non-spastic(non-CNS), peripheral or localized symptoms are commonly treated withso-called “antispasmodic” or “spasmolytic” agents, but these generallyare not useful in treating spasticity. Cedarbaum & Schleifer, “Drugs forParkinson's Disease, Spasticity and Acute Muscle Spasms,” in GOODMAN ANDGILMAN'S THE PHARMACOLOGICAL BASIS OF THERAPEUTICS, 8th ed. [hereafterGOODMAN AND GILMAN'S], pages 463-484 (Pergamon Press 1990).

The compositions of matter and pharmaceutical formulations andcompositions employed in accordance with the present invention caneffect a centrally mediated decrease in muscle tone and, hence, areuseful for the acute or chronic alleviation of one or more symptoms orside effects of spasticity. In this context, “spasticity” refers to aheightened tone of skeletal muscle with is manifested by symptoms suchas, but not limited to, painful flexor or extensor spasms, increased orexaggerated deep-tendon reflexes, hyperreflexia, loss of dexterity,muscular weakness, exaggerated tendon jerks, and clonus. The phrase“antispasticity agent” refers here to a composition that is useful forthe symptomatic treatment of spasticity, as demonstrated by thealleviation of at least one of the following manifestations or sideeffects of spasticity: painful flexor or extensor spasms, increased orexaggerated deep-tendon reflexes, hyperreflexia, loss of dexterity,muscular weakness, exaggerated tendon jerks, and clonus, or thereduction of the frequency of these manifestations or side effects.

Accordingly, the “alleviation” of spasticity refers here to thelessening of one or more symptoms of spasticity, including, but notlimited to, painful flexor or extensor spasms, increased or exaggerateddeep-tendon reflexes, hyperreflexia, loss of dexterity, muscle weakness,exaggerated tendon jerks, and clonus, or the reduction of the frequencyof these manifestations or side effects.

AFFECTIVE MOOD DISORDERS: These include conditions ranging fromdepression to dysphoric mania, for example, mania, schizoaffectivedisorder, traumatic brain injury-induced aggression, post-traumaticstress disorder, bipolar mood disorder, panic states, and behavioraldyscontrol syndromes. See Emrich et al., J. Affective Disorders8:243-250 (1985) and Bernasconi et al., in ANTICONVULSANTS IN AFFECTIVEDISORDERS, pages 14-32 (Excerpta Medica 1984). The novel compositionsand pharmaceutical formulations and compositions according to thepresent invention are effective in the treatment of these diseases,disorders, and conditions, and should exhibit improved side effectprofiles when compared to currently existing therapeutic agents in thistherapeutic category.

NEUROPATHIC PAIN SYNDROMES: Conditions in this category, involving“neuropathic pain,” affect a significant number of patients sufferingfrom disorders of the brain or spinal cord, such as stroke, trauma,multiple sclerosis, and diabetes. Casey, in PAIN AND CENTRAL NERVOUSSYSTEM DISEASE (Raven 1991). The use of anticonvulsants to treat variouspain states has been documented extensively. Swendlow, J. Clin.Neuropharmacol. 7: 51-82 (1984). Thus, a novel composition orpharmaceutical formulation or composition of the present invention canbe applied in similar fashion to ameliorate neuropathic pain.

HEADACHES: Headaches of the migraine type [Hering and Kuritzky,Cephalagia 12: 81-84 (1992)], the cluster type [Hering and Kuritzky,loc. cit. 9:195-198 (1989)], and the chronic type [Mathew and Sabiha,Headache 31: 71-74 (1991)] have been treated with anticonvulsants. Thecompositions and formulations of the present invention can therefore beused to alleviate the symptoms associated with each of these threeheadache types, without the adverse side effects of current existingtherapies.

RESTLESSNESS SYNDROME: The phrase “restlessness syndrome” denotes asomatic (non-mental) restlessness characterized by involuntary movementof the limbs, as well as by a sense of physical (rather than mental)agitation, which is independent of mood and, hence, is distinguishedfrom restlessness per se. [See Sachev et al., Austral. New Zealand J.Psychiatry 30:38-53 (1996)].

Restlessness syndromes, inclusive of numerous indications, can beobserved in association with many organic and non-organic psychiatricillnesses. For example, drug-induced restlessness (tardive, chronic, andwithdrawal akathisias), such as drug-induced extrapyramidal symptoms, isone of the most common side effects of neuroleptic drug therapy. Alsowithin the restlessness-syndrome rubric are the so-called “restless legsyndrome” and “sleep-related periodic leg movements,” pathologies thatcan be associated with head and/or spinal cord trauma and with lesionsof the spinal cord. Idiopathic restless leg syndrome follows anautosomal dominant inheritance, with a variable clinical expression ofsymptoms. See O'Keefe, Arch. Intern. Med. 156: 243-248 (1996); Danek etal., in NEUROLOGICAL DISORDERS: COURSE AND TREATMENT, pages 819-823(Academic Press 1996); Mellick and Mellick, Neurology 45(suppl.):285-286 (1995). The present invention provides an effective therapy forrestlessness syndromes with minimal side effects.

MOVEMENT DISORDERS: Various agents are known to decrease the dyskineticmovement characterizing movement disorders such as Parkinson's disease,Huntington's chorea, Alzheimer's disease, tardive dyskinesia, andstiff-man syndrome. Lloyd and Morselli, in PSYCHOPHARMACOLOGY: THE THIRDGENERATION OF PROGRESS (Raven Press 1987). A therapy within the presentinvention alleviates one or more symptoms of a movement disorder.

The compounds of the invention may also be useful as anxiety-reducing(anxiolytic) agents.

By “neurological disorder or disease” is meant a disorder or disease ofthe nervous system including, but not limited to, epilepsy, anxiety,multiple sclerosis, strokes, head trauma, spinal cord injuries, andchronic neurodegenerative diseases such as Parkinson's and Huntington'sdiseases, Alzheimer's disease, and amyotrophic lateral sclerosis. Alsomeant by “neurological disorder or disease” are those disease states andconditions in which an antispastic or anticonvulsant may be indicated,useful, recommended and/or prescribed.

By “neurodegenerative disease” is meant diseases such as, but notlimited to, Huntington's Disease, Parkinson's Disease, Alzheimer'sDisease, and amyotrophic lateral sclerosis (ALS).

By “anticonvulsant” is meant a compound capable of reducing theseverity, number, or duration of convulsions produced, observed, orfound in conditions such as generalized tonic-clonic seizures, absenceseizures, myoclonic seizures, simple partial seizures, complex partialseizures, secondarily generalized partial seizures, status epilepticus,and trauma-induced seizures as occur following head injury or surgery.

By “anticonvulsant activity” is meant efficacy in reducing the severity,number, or duration of convulsions produced, observed, or found inconditions such as generalized tonic-clonic seizures, absence seizures,myoclonic seizures, simple partial seizures, complex partial seizures,secondarily generalized partial seizures, status epilepticus, andtrauma-induced seizures, as occur following head injury or surgery.

By “therapeutic dose” is meant an amount of a compound that relieves tosome extent one or more symptoms of the disease or condition of thepatient. Additionally, by “therapeutic dose” is meant an amount thatreturns to normal, either partially or completely, physiological orbiochemical parameters associated with or causative of the disease orcondition. Generally, it is an amount between about 0.1-15-20-30 mg/kgbody weight, depending on the age, size, and disease associated with thepatient. The dosing can be one to four times a day.

By “pharmaceutical composition” is meant a therapeutically effectiveamount of a compound of the present invention in a pharmaceuticallyacceptable carrier, i.e., a formulation to which the compound can beadded to dissolve or otherwise facilitate administration of thecompound. Examples of pharmaceutically acceptable carriers includewater, saline, and physiologically buffered saline. Such apharmaceutical composition is provided in a suitable dose. Suchcompositions are generally those which are approved for use in treatmentof a specific disorder by the FDA or its equivalent in non-U.S.countries.

It is understood that certain of the compounds of the present inventionhave one or more chiral stereocenter(s). Such compounds may demonstratepreferred biological activity as a racemic (or diastereomeric) mixture,as a mixture of R and S enantiomers (or diastereomers), or as pureenantiomers (R or S) (or diastereomers). When one pure enantiomer showspreferred biological activity, it is this preferred enantiomer isreferred to as the eutomer, whereas the less preferred, lessbiologically active enantiomer is referred to as the distomer.

METHODS FOR PREPARING PHARMACEUTICAL FORMULATIONS AND COMPOSITIONS, ANDMETHODS FOR ADMINISTRATION: As demonstrated herein, usefulpharmaceutical formulations and compositions of this invention may beused to treat neurological disorders or diseases. While thesepreparations will typically be used in therapy for human patients, theymay also be used to treat similar or identical diseases in othervertebrates such as other primates, domestic animals, farm animals suchas swine, cattle, and poultry, and sports animals and pets such ashorses, dogs, and cats.

The present invention also is directed to pharmaceutical formulationsand compositions containing combinations of two or more of the activecompounds described above. The compounds of the present invention can beprepared (formulated) according to known methods for preparingpharmaceutically useful compositions, whereby active agents are combinedin a mixture with a pharmaceutically acceptable carrier(s). Forinstance, see Gennaro (Ed.), REMINGTON'S PHARMACEUTICAL SCIENCES, 18thed. (Mack Publishing Co., Easton, Pa., 1990) and GOODMAN AND GILMAN'STHE PHARMACOLOGICAL BASIS OF THERAPEUTICS. A compound and/or acomposition is said to be in a “pharmaceutically acceptable carrier” ifits administration can be tolerated by a recipient patient. Sterilephosphate-buffered saline is one example of a pharmaceuticallyacceptable carrier. Other suitable carriers (e.g., saline and Ringer'ssolutions) are well known to those skilled in the art (see below).

The pharmaceutically acceptable carrier includes a suitable excipientand/or auxiliary whose administration is tolerated by the patient.Pharmaceutically acceptable carriers which are known in the art include,but are not limited to, calcium carbonate, calcium phosphate, calciumsulfate, sucrose, dextrose, lactose, fructose, xylitol, sorbitol,starch, starch paste, cellulose derivatives, gelatin,polyvinylpyrrolidone, sodium chloride, dextrins, stearic acid, magnesiumstearate, calcium stearate, vegetable oils, polyethylene glycol, sterilephosphate-buffered saline, saline, and Ringer's solutions, and mixturesthereof. See, for example, REMINGTON'S PHARMACEUTICAL SCIENCES, supra.

Pharmaceutically acceptable salts of organic acids (such as amino acids)which have been approved by the U.S. Food and Drug Administration forcommercial marketing include sodium, potassium, lithium, zinc, aluminum,calcium, and magnesium salts. See REMINGTON'S PHARMACEUTICAL SCIENCES,18th ed., page 1445 (Mack Publishing Co. 1990).

The compounds of the present invention and pharmaceutical compositionsthereof are formulated as known in the art. For instance, thecompound(s) of the present invention may be combined with apharmaceutically acceptable carrier(s) and processed into a desireddosage form. The pharmaceutical compositions of the present inventionmay be produced or manufactured in a manner that is itself known, e.g.,by means of conventional mixing, dissolving, granulating, dragee-making,levigating, emulsifying, encapsulating, entrapping, or lyophilizingprocesses which involve both the pharmaceutical composition of interestand its pharmaceutically acceptable carrier.

In general, the dosages of the compounds, formulations, and compositionsdescribed herein will vary depending upon such factors as the patient'sage, weight, height, sex, general medical condition, and previousmedical history. For purposes of therapy, a composition of the presentinvention and a pharmaceutically acceptable carrier are administered toa subject in need of such treatment in a therapeutically effectiveamount. The combination of active agents and carrier (formulation orcomposition) is said to be administered in a “therapeutically effectiveamount” if the amount administered is physiologically significant. Apharmaceutical composition is physiologically significant if itspresence results in a detectable change in the physiology of a recipientpatient. In the present context, for example, an anticonvulsantcomposition is physiologically significant if the presence of thecomposition results in the alleviation of one or more symptoms ofepilepsy, such as seizures and/or convulsions. Further, the dose andperhaps dose frequency, will also vary according to the age, bodyweight, and response of the individual patient. A program comparable tothat discussed above may be used in veterinary medicine.

The compounds of the present invention can be administered orally usingsolid oral dosage forms such as, for example, enteric-coated tablets,caplets, gelcaps, sprinkles, or capsules, or via liquid oral dosageforms such as syrups or elixirs. Unit solid oral dosage forms preferablycontain appropriate amounts of active compounds per tablet or capsulesuch that they can be taken 1-2 at a time for a maximum of two times perday. Liquid formulations can also be employed with active compounds soas to provide 1-2 teaspoonfuls per dose. Furthermore, correspondingreduced dosage pediatric chewable and liquid oral dosage forms can alsobe prepared and administered. These compounds can also be added to foodsand beverages in the form of drops (with a dropper from a “concentrate”preparation) for oral administration. In addition, the compounds of thepresent invention may also be formulated into chewing gum to facilitateoral delivery and absorption. Appropriate dosages for each of thecompounds used in the formulations and compositions of the presentinvention can be discerned from the foregoing descriptions by thoseskilled in the art.

Alternatively, the compounds of the present invention can beadministered by injection or other systemic routes, such as transdermalor transmucosal administration, for example, nasally, sublingually,buccally, vaginally, or rectally, via suppositories. Other routes ofadministration (e.g., useful in veterinary applications) includeintestinal and parenteral delivery, including intramuscular,subcutaneous, and/or intramedullary injections, as well as intrathecal,direct intracerebroventricular, intravenous, intraperitoneal,intranasal, or intraocular injections. Oral administration is much moreconvenient, however, and therefore is preferred.

The present invention thus contemplates a variety of compounds that aresuitable for oral, parenteral, transdermal, transmucosal, intranasal,sublingual, buccal, or rectal administration. It is further understoodthat the compounds of the present invention can be used in combinationwith other pharmaceutically active ingredients to prepare still othernovel pharmaceutical compositions.

DEMONSTRATING THERAPY-IMPLICATING AND THERAPEUTICALLY RELEVANT ACTIVITY:The suitability and therapeutic effectiveness of a given pharmaceuticalformulation or composition for the alleviation of symptoms, as discussedabove, can be demonstrated by using the animal models, testing, andscreening methods which are described in, e.g., U.S. Pat. Nos.6,589,994, 6,617,358, and 7,265,155, which are hereby incorporatedherein in their entirety.

The therapeutic effects of the compounds of the invention describedabove, combined with a general lack of toxicity, make the compounds ofthe present invention ideal agents for the treatment of the conditionsdescribed above. With this background, the present invention will beunderstood more readily by those skilled in the art by reference to theexamples below, which are provided for purposes of illustration and arenot intended to be limiting of the invention.

EXAMPLES Example 1 Preparation of Compound A[3-(4-Chlorophenyl)-3-methylbutyramide]

A solution of 3-(4-chlorophenyl)-3-methylbutyric acid (6.1 g, 41.9 mmol)in CH₂Cl₂ (100 mL) and DMF (0.2 mL) was treated with oxalyl chloride(5.2 mL, 7.45 mmol) at 0° C. under static nitrogen. The reactionsolution was stirred at room temperature overnight under nitrogen. Theexcess dichloromethane was removed under reduced pressure. The resultingresidue was azeotroped by toluene (50 mL).

Ammonia (gas) was bubbled through the solution of the acid chloride[3-(4-chlorophenyl)-3-methylbutyryl chloride] in anhydrous THF (100 mL)at 5 degrees Celsius for 15 minutes. The reaction mixture was stirredovernight at room temperature under static nitrogen.

The white precipitate (ammonium chloride) was filtered and washed withTHF (100 mL). The filtrate and wash-solution were combined andevaporated under reduced pressure. The resulting white solid wasre-dissolved in ethyl acetate (300 mL). The ethyl acetate layer waswashed with H₂O, 1.0 M HCl, a saturated solution of sodium bicarbonate,and brine solution. The ethyl acetate solution was then dried overmagnesium sulfate, filtered, and evaporated under reduced pressure. Theresulting white solid was triturated with a chilled solution of diethylether and hexane (50:50). This afforded 4.22 g of white flakes[3-(4-chlorophenyl)-3-methylbutyramide] (69% yield). This material wasdetermined to be 100% pure by GC/MS analysis. ¹H NMR spectroscopy gavesignals consistent with the product's structure and indicated greaterthan 98% purity.

Example 2 Preparation of Compound B[3-(4-Chlorophenyl)-3,N-dimethylbutyramide]

A solution of 3-(4-chlorophenyl)-3-methylbutyric acid (5.95 g, 28 mmol)in CH₂Cl₂ (100 mL) and DMF (0.2 mL) was treated with oxalyl chloride(5.2 mL, 7.45 mmol) at 0° C. under static nitrogen. The reactionsolution was stirred at room temperature overnight under nitrogen. Theexcess dichloromethane was removed under reduced pressure. The resultingresidue was azeotroped by toluene (50 mL).

The residue was dissolved in 150 mL of dry THF and treated withmethylamine solution (2.0 M in THF, 45 mL, 84 mmol) at 5 degreesCelsius. The reaction mixture was stirred overnight at room temperatureunder static nitrogen.

The white precipitate was filtered and washed with THF (100 mL). Thefiltrate and wash-solution were combined and evaporated under reducedpressure. The resulting white solid was re-dissolved in diethyl ether(300 mL). The ether layer was washed with H₂O, 1.0 M HCl, a saturatedsolution of sodium bicarbonate, and brine solution. The ether solutionwas then dried over magnesium sulfate, filtered, and evaporated underreduced pressure. The resulting white solid was triturated with achilled solution of diethyl ether and hexane (50:50). This afforded 5.46g of white flakes [3-(4-chlorophenyl)-3,N-dimethylbutyramide] (86%yield). This material was determined to be 100% pure by GC/MS analysis.¹H NMR spectroscopy gave signals consistent with the product's structureand indicated greater than 98% purity.

Example 3 Preparation of Compound C [(R)-3-Phenylbutyramide]

A solution of (R)-3-phenylbutyric acid (4 g, 24.36 mmol) in CH₂Cl₂ (75mL) and DMF (0.1 mL) was treated with oxalyl chloride (3.0 mL, 34.0mmol) at 0° C. under static nitrogen. The reaction solution was stirredat room temperature overnight under nitrogen. The excess dichloromethanewas removed under reduced pressure. The resulting residue was azeotropedby toluene (50 mL).

Ammonia (gas) was bubbled through the solution of the acid chloride[(R)-3-phenylbutyrl chloride] in anhydrous THF (100 mL) at 5 degreesCelsius for 15 minutes. The reaction mixture was stirred overnight atroom temperature under static nitrogen.

The white precipitate (ammonium chloride) was filtered and washed withTHF (100 mL). The filtrate and wash-solution were combined andevaporated under reduced pressure. The resulting white solid wasre-dissolved in ethyl acetate (300 mL). The ethyl acetate layer waswashed with H₂O, 1.0 M HCl, a saturated solution of sodium bicarbonate,and brine solution. The ethyl acetate solution was then dried overmagnesium sulfate, filtered, and evaporated under reduced pressure.Crude material was purified using a Biotage SP4 System (Column Si 40+M0344-1, 95:5, CH₂Cl₂: MeOH). The resulting off-white solid wastriturated with a chilled solution of diethyl ether and hexane (50:50).This afforded 2.9 g of white solid [(R)-3-phenylbutyramide] (73% yield).This material was determined to be 100% pure by GC/MS analysis. ¹H NMRspectroscopy gave signals consistent with the product's structure andindicated greater than 98% purity.

Example 4 Preparation of Compound D [3-(3-Fluorophenyl)butyramide]

In a 3-necked, 500-mL round-bottomed flask, a suspension of sodiumhydride (60% in oil, 1.1 eq. 80 mmol, 3.20 g) in N,N-dimethylformamide(DMF, 100 mL) under nitrogen was treated drop-wise with a solution oftriethyl phosphonoacetate (1.2 eq. 87 mmol, 19.50 g) in DMF (50 mL).After the addition, the reaction mixture was heated in a water bath(100° C.) until all visible signs of the sodium hydride were gone (30minutes). The mixture was cooled to ambient temperature and then treatedwith a solution of 3′-fluoroacetophenone (1.0 eq. 10 g, 72.4 mmol) inDMF (50 mL). The reaction mixture was stirred for 2 hours at ambienttemperature and a 1-mL aliquot was removed and quenched in water (˜2mL). Diethyl ether (˜2 mL) was added to this and the mixture wasequilibrated. Analysis of the organic layer by GC/MS showed completeconsumption of the starting benzophenone. As a result, the reactionmixture was quenched by the addition of water. The mixture wastransferred to a large round-bottomed flask and the majority of thesolvents were removed using a rotary evaporator. The mixture was cooledand transferred to a separatory funnel using [a] diethyl ether (500 mL)and water (250 mL). The mixture was equilibrated and the aqueous layerwas removed. The organic layer was washed an additional 3 times withwater (3×250 mL). GC/MS analysis of this solution showed only product(with no remaining phosphonoacetate). The organic solution was driedover anhydrous MgSO₄, filtered, and concentrated to afford 18.09 g ofcrude material (containing oil from the sodium hydride).

A solution of crude of [3-(3-fluorophenyl)-but-2-enoic acid ethyl ester](9 g, 0.015 mmol) in methanol (75 mL) was treated with Pd/C (10%, 450mg). The reaction mixture was subjected to hydrogenation at 45 psi for 1hour. The reaction mixture was passed through a Celite plug to removepalladium on carbon. The filtrate was concentrated under reducedpressure. This afforded 10.1 g of a colorless oil[3-(3-fluorophenyl)butyric acid ethyl ester]. The material wasdetermined to be 94% pure by GC/MS analysis. This product was usedwithout purification (to remove mineral oil).

A crude solution of 3-(3-fluorophenyl)butyric acid ethyl ester, 10.1 g,48 mmol] in ethanol (50 mL) was treated with 10 M NaOH solution (50 mL,857 mmol). The reaction mixture was refluxed overnight. The reactionmixture was dried under reduced pressure in order to get rid of theethyl alcohol. The resulting residue was re-dissolved in 150 mL ofwater. The mixture was transferred to a separatory funnel using water(50 mL) and diethyl ether (200 mL). The mixture was equilibrated and theether layer was removed. The aqueous layer was acidified by HCl solution(pH˜2) and extracted with diethyl ether (300 mL). The organic layer wasdried over magnesium sulfate, filtered, and concentrated under reducedpressure. This afforded 8.1 g of an orange viscous oil,3-(3-fluorophenyl)butyric acid (92.6% yield). This material wasdetermined to be 100% pure by GC/MS analysis.

A solution of 3-(3-fluorophenyl)butyric acid (8.1 g, 44.46 mmol) inCH₂Cl₂ (100 mL) and DMF (0.7 mL) was treated with oxalyl chloride (5.43mL, 7.9 mmol) at 0° C. under static nitrogen. The reaction solution wasstirred at room temperature overnight under nitrogen. The excessdichloromethane was removed under reduced pressure. The resultingresidue was azeotroped by toluene (70 mL).

Ammonia (gas) was bubbled through the solution of the acid chloride[3-(3-fluoro-phenyl)butyryl chloride] in anhydrous THF (100 mL) at 5degrees Celsius for 15 minutes. The reaction mixture was stirredovernight at room temperature under static nitrogen.

The white precipitate (ammonium chloride) was filtered and washed withTHF (200 mL). The filtrate and wash-solution were combined andevaporated under reduced pressure. The resulting white solid wasre-dissolved in ethyl acetate (350 mL). The ethyl acetate layer waswashed with H₂O, 1.0 M HCl, a saturated solution of sodium bicarbonate,and brine solution. The ethyl acetate solution was then dried overmagnesium sulfate, filtered, and evaporated under reduced pressure. Theresulting white solid was triturated with a chilled solution of diethylether and hexane (50:50). This afforded 6.8 g of off-white powder of3-(3-fluorophenyl)butyramide (84% yield). This material was determinedto be 100% pure by GC/MS analysis (a mixture of R and S enantiomers).¹H-NMR spectroscopy gave signals consistent with the product's structureand indicated greater than 98% purity.

Examples 5-14 Preparation of Compounds E-N

Compounds E-N were prepared using the corresponding acetophenones (shownin Table 1 below) with the method used for the preparation of Compound Din Example 4, above. In addition, Compound M (Example 13) and Compound N(Example 14) were prepared using the corresponding amines, i.e.,methylamine and dimethylamine, respectively. All of the final productswere determined to be 100% pure by GC/MS analysis. ¹H-NMR spectroscopyof each final product gave signals consistent with its structure andindicated greater than 98% purity.

TABLE 1 Example Weight % No. Formula (g) Yield Product Chemical NameCorresponding Acetophenone 5 E 3.2 91 3-(4-fluorophenyl)-4′-fluoroacetophenone butyramide 6 F 5.7 79 3-[4-(trifluoromethyl)-4′-(trifluoromethyl)acetophenone phenyl]butyramide 7 G 6.8 843-[3-(trifluoromethyl)- 3′-(trifluoromethyl)acetophenonephenyl]butyramide 8 H 3.8 81 3-[4-(trifluoromethoxy)-4′-(trifluoromethoxy)acetophenone phenyl]butyramide 9 I 1.9 863-[3-(trifluoromethoxy)- 3′-(trifluoromethoxy)acetophenonephenyl]butyramide 10 J 2.3 84 3-(3-chloro-4-methoxy-3′-chloro-4′-methoxyacetophenone phenyl)butyramide 11 K 3.6 70 3-(3,4-3′,4′-ethylenedioxyacetophenone ethylenedioxyphenyl)- butyramide 12 M2.5 91 3-(3,4- 3′,4′-methylenedioxyacetophenone methylenedioxyphenyl)-butyramide 13 M 2.7 90 N-methyl-3-(3,4- 3′,4′-methylenedioxyacetophenonemethylenedioxy- phenyl)butyramide 14 N 2.3 73 N,N-dimethyl-3-(3,4-3′,4′-methylenedioxyacetophenone methylene- dioxyphenyl)butyramide

Example 15 Preparation of Compound O [3-(4-Cyanophenoxy)butyramide]

A solution of 4 g (0.1 mol) of sodium hydroxide in 100 mL of H₂O and11.9 g (0.1 mol) of 4-cyanophenol was heated at reflux for 15 minutes.β-Butyrolactone (8.6 g, 0.1 mol) was added to the refluxing solutionover 15 hours. The reaction was then cooled to room temperature. Thereaction solution was transferred to a separatory funnel using water(200 mL) and diethyl ether (200 mL). The mixture was equilibrated andthe ether layer was removed. The aqueous layer was acidified by HClsolution (pH˜2) and extracted with ethyl acetate (300 mL). The ethylacetate layer was dried over magnesium sulfate, filtered, andconcentrated under reduced pressure to afford 10.78 g of crude product.This crude material was purified using a Biotage SP4 System (Column Si65i, 9:1 CH₂Cl₂:MeOH), which afforded 9.87 g of a pale-yellow viscousoil [3-(4-cyanophenoxy)butyric acid], which solidified upon standing atroom temperature. This material was determined to be 96% pure by GC/MSanalysis. This material was used without further purification.

A crude solution of [3-(4-cyanophenoxy)butyric acid] (10.8 g, 52.6 mmol)in CH₂Cl₂ (100 mL) and DMF (0.21 mL) was treated with oxalyl chloride (6mL, 68.4 mmol) at 0° C. under static nitrogen. The reaction solution wasstirred at room temperature overnight under nitrogen. The excessdichloromethane was removed under reduced pressure.

Ammonia (gas) was bubbled through the solution of the acid chloride[3-(4-cyanophenoxy)butyryl chloride] in anhydrous CH₂Cl₂ (150 mL) at 5degrees Celsius for 15 minutes. The reaction mixture was stirredovernight at room temperature under static nitrogen.

The white precipitate (ammonium chloride) was filtered and washed withCH₂Cl₂ (100 mL). The filtrate and wash-solution were combined andevaporated under reduced pressure. The resulting white solid wasre-dissolved in ether (250 mL). The ether layer washed with H₂O, 1.0 MHCl, a saturated solution of sodium bicarbonate, and brine solution. Theether solution was then dried over magnesium sulfate, filtered, andevaporated under reduced pressure. Crude material was purified using aBiotage SP4 System (Column Si 40+M 0344-1, 95:5, CH₂Cl₂:MeOH). Thisafforded 2.987 g of an off-white solid [3-(4-cyanophenoxy)butyramide](29% yield). This material was determined to be 97% pure by GC/MSanalysis. ¹H NMR spectroscopy gave signals consistent with the product'sstructure and indicated greater than 98% purity.

Example 16 Preparation of Compound P[(1R,2R)-trans-2-phenylcyclopropane-1-carboxamide]

A solution (1R,2R)-trans-2-phenylcyclopropane-1-carboxylic acid (2.1 g.,12.8 mmol) in CH₂Cl₂ (50 mL) and DMF (0.20 mL) was treated with oxalylchloride (1.5 mL, 16.7 mmol) at 0° C. under static nitrogen. Thereaction solution was stirred at room temperature overnight undernitrogen. The excess dichloromethane was removed under reduced pressure.

Ammonia (gas) was bubbled through the solution of the acid chloride[(1R,2R)-trans-2-phenylcyclopropane-1-carboxyl chloride] in anhydrousCH₂Cl₂ (100 mL) at 5 degrees Celsius for 15 minutes. The reactionmixture was stirred overnight at room temperature under nitrogen.

The reaction mixture was evaporated under reduced pressure and theresulting residue re-dissolved in an ethyl acetate/water mixture. Themixture was transferred to a separatory funnel using H₂O (60 mL) andethyl acetate (100 mL). The mixture was equilibrated and the aqueousphase was removed. The organic layer was washed with 1.0 M HCl (10 mL),H₂O (70 mL), and brine (75 mL), consecutively. The organic layer wasdried over anhydrous magnesium sulfate, filtered, and [the] excesssolvent was removed under reduced pressure. The resulting light-brownsolid was purified using a Biotage SP4 System (Column Si 40+S 90:10CH₂Cl₂:MeOH), which afforded 1.127 g of white powder[(1R,2R)-trans-2-phenylcyclopropane-1-carboxamide] (54% yield). Thismaterial was determined to be 100% pure by GC/MS analysis. ¹H-NMRspectroscopy gave signals consistent with the product's structure andindicated greater than 98% purity.

Example 17 Preparation of Compound Q[(1R,2R)-2-Phenylcyclopropane-carboxylicacid-((S)-1-carbamoyl-3-methylbutyl)amide]

A solution of (1R,2R)-trans-2-phenylcyclopropane-1-carboxylic acid(0.905 g., 5.6 mmol) in CH₂Cl₂ (30 mL) and DMF (0.05 mL) was treatedwith oxalyl chloride (0.65 mL, 7.23 mmol) at 0° C. under staticnitrogen. The reaction solution was stirred at room temperatureovernight under nitrogen. The excess dichloromethane was removed underreduced pressure.

The solution of the acid chloride[(1R,2R)-trans-2-phenylcyclopropane-1-carboxyl chloride] in CH₂Cl₂ (50mL) was added drop-wise in to a solution of H-Leu-NH₂ [L-leucine amide,(S)-2-amino-4-methyl-n-valeramide] (0.761 g, 5.8 mmol) and triethylamine(1.13 g, 11.1 mmol) in CH₂Cl₂ (60 mL) at zero degrees Celsius. Thereaction mixture was stirred at room temperature under nitrogenovernight.

The reaction mixture was evaporated under reduced pressure and theresulting residue was re-dissolved in an ethyl acetate/water mixture.The mixture was transferred to a separatory funnel using H₂O (50 mL) andethyl acetate (80 mL). The mixture was equilibrated and the aqueousphase was removed. The organic layer was washed with 1.0 M HCl (20 mL),H₂O (90 mL), and brine (120 mL), consecutively. The organic layer wasdried over anhydrous magnesium sulfate, filtered, and the excess solventwas removed under reduced pressure. The resulting orange-brown solid waspurified using a Biotage SP4 System (Column Si 40+M 90:10, CH₂Cl₂:MeOH),which afforded 0.365 g of white powder[(1R,2R)-2-phenylcyclopropanecarboxylicacid-((S)-1-carbamoyl-3-methylbutyl)-amide] (24% yield). This materialwas determined to be 100% pure by GC/MS analysis. ¹H-NMR spectroscopygave signals consistent with the product's structure and indicatedgreater than 98% purity.

Example 18 Preparation of Compound U[2-[1-(4-Methoxyphenyl)cyclopropyl]-acetamide]

A stirred suspension of lithium aluminum hydride (0.211 mol) inanhydrous ether (200 mL) is treated with1-(4-methoxyphenyl)-1-cyclopropanecarboxylic acid (0.1406 mol) in 100 mLof ether at 0° C. The reaction mixture is then stirred at roomtemperature under nitrogen overnight. The reaction mixture is quenchedby the drop-wise addition of 100 mL of deionized H₂O. The mixture isfiltered and the cake solid is washed with diethyl ether (1 L). Thefiltrate mixture (ether and water) is transferred into a separatoryfunnel. The organic layer is separated from the aqueous layer and washedwith brine solution. The ether layer is dried over magnesium sulfate,filtered, and concentrated under reduced pressure at room temperature.This affords [1-(4-methoxy-phenyl)-cyclopropyl]-methanol.

A neat solution of [1-(4-methoxyphenyl)cyclopropyl]methanol (0.074 mol)is treated with phosphorous tribromide (0.081 mol) drop-wise at 0° C.under static nitrogen. The reaction solution is heated to 130° C. andthe temperature is maintained for 6 hours. The reaction mixture iscooled down to room temperature and the orange precipitate is filteredoff. The orange precipitate is washed with 200 mL of diethyl ether. Thefiltrate is transferred into a separatory funnel using 150 mL of waterand 200 mL of diethyl ether. The mixture is equilibrated and the aqueouslayer is extracted one more time with 200 mL of diethyl ether. The etherextracts and ether-wash are combined and washed with saturated sodiumbicarbonate solution and brine. Then the ether extracts are dried overmagnesium sulfate and the excess diethyl ether is removed under reducedpressure at 30° C. This affords1-(1-bromomethyl-cyclopropyl)-4-methoxybenzene. The crude material isconverted into the corresponding nitrile without further purification.

A crude solution of 1-(1-bromomethyl-cyclopropyl)-4-methoxybenzene (60.3mmol) in dimethyl sulfoxide (60 mL) is treated with sodium cyanide(180.7 mmol). The reaction mixture is heated to 95 degrees Celsiusovernight under nitrogen. The reaction mixture is transferred to aseparatory funnel using brine (150 mL) and chloroform (300 mL). Thereaction mixture is equilibrated and the aqueous layer is removed. Theaqueous layer is extracted an additional two times with chloroform(2×300 mL). The combined organic extract is dried over anhydrous MgSO₄,filtered, and concentrated under reduced pressure to afford[1-(4-methoxyphenyl)cyclopropyl]acetonitrile. This crude material isused in the next step (hydrolysis of the nitrile to the correspondingamide) without further purification. [Alternatively, the correspondingcarboxylic acid can be obtained from this material by acid hydrolysis(e.g., using sulfuric acid).]

A solution of [1-(4-methoxyphenyl)cyclopropyl]acetonitrile (60.4 mmol)in DMSO (75 mL) is treated with H₂O₂ (50% w/w) (434 mmol) and potassiumcarbonate (121 mmol) at zero degrees Celsius. The reaction mixture isstirred at room temperature over the weekend. The reaction mixture istransferred into a separatory funnel using water (100 mL) and CH₂Cl₂(200 mL). The mixture is equilibrated and the CH₂Cl₂ layer is removed.The aqueous layer is extracted two additional times with CH₂Cl₂ (2×300mL). The combined CH₂Cl₂ extracts are washed 5 consecutive times withwater (5×200 mL) followed by a brine (500 mL) wash, dried over anhydrousMgSO₄, filtered, and concentrated under reduced pressure, which affords2-[1-(4-methoxyphenyl)-cyclopropyl]-acetamide.

Example 19 Preparation of Compound V[3-(4-Chlorophenoxy)-3-methylbutyr-amide]

A stirred suspension of lithium aluminum hydride (0.211 mol) inanhydrous ether (200 mL) is treated with2-(4-chlorophenoxy)-2-methylpropanic acid (0.1406 mol) in 100 mL ofether at 0° C. The reaction mixture is stirred at room temperature undernitrogen overnight. The reaction mixture is quenched by the drop-wiseaddition of 100 mL of deionized H₂O. The mixture is filtered and thecake solid is washed with diethyl ether (1 L). The filtrate mixture(ether and water) is transferred into a separatory funnel. The organiclayer is separated from the aqueous layer and washed with brinesolution. The ether layer is dried over magnesium sulfate, filtered, andconcentrated under reduced pressure at room temperature. This affords2-(4-chlorophenoxy)-2-methylpropan-1-ol.

A neat solution of 2-(4-chlorophenoxy)-2-methylpropan-1-ol (0.074 mol)is treated with phosphorous tribromide (0.081 mol) drop-wise at 0° C.under static nitrogen. The reaction solution is heated to 130° C. andthe temperature is maintained for 6 hours. The reaction mixture iscooled down to room temperature and the orange precipitate is filteredoff. The orange precipitate is washed with 200 mL of diethyl ether. Thefiltrate is transferred into a separatory funnel using 150 mL of waterand 200 mL of diethyl ether. The mixture is equilibrated and the aqueouslayer is extracted one more time with 200 mL of diethyl ether. The etherextracts and ether-wash are combined and washed with saturated sodiumbicarbonate solution and brine. Then the ether extract is dried overmagnesium sulfate and the excess diethyl ether is removed under reducedpressure at 30° C. This affords1-(2-bromo-1,1-dimethylethoxy)-4-chlorobenzene. The crude1-(2-bromo-1,1-dimethylethoxy)-4-chlorobenzene is converted into thecorresponding nitrile without further purification.

A crude solution of 1-(2-bromo-1,1-dimethylethoxy)-4-chlorobenzene (60.3mmol) in dimethyl sulfoxide (60 mL) is treated with sodium cyanide(180.7 mmol). The reaction mixture is heated to 95 degrees Celsiusovernight under nitrogen. The reaction mixture is transferred into aseparatory funnel using brine (150 mL) and chloroform (300 mL). Thereaction mixture is equilibrated and the aqueous layer is removed. Theaqueous layer is extracted an additional two times with chloroform(2×300 mL). The combined organic extracts are dried over anhydrousMgSO₄, filtered, and concentrated under reduced pressure to afford3-(4-chlorophenoxy)-3-methylbutyronitrile. This crude material is usedin the next step (hydrolysis of the nitrile into the correspondingamide) without further purification. [Alternatively, the correspondingcarboxylic acid can be obtained from this material by acid hydrolysis(e.g., using sulfuric acid).]

A solution of 3-(4-chlorophenoxy)-3-methylbutyronitrile (60.4 mmol) inDMSO (75 mL) is treated with H₂O₂ (50% w/w) (434 mmol) and potassiumcarbonate (121 mmol) at zero degrees Celsius. The reaction mixture isstirred at room temperature over the weekend. The reaction mixture istransferred into a separatory funnel using water (100 mL) and CH₂Cl₂(200 mL). The mixture is equilibrated and the CH₂Cl₂ layer is removed.The aqueous layer is extracted two additional times with CH₂Cl₂ (2×300mL). The combined CH₂Cl₂ extracts are washed 5 consecutive times withwater (5×200 mL) followed by a brine (500 mL) wash, dried over anhydrousMgSO₄, filtered, and concentrated under reduced pressure, which affords3-(4-chlorophenoxy)-3-methylbutyramide.

Example 20 Preparation of Compound AG[(R)-3-(4-Trifluoromethylphenyl)-butyramide]

Acetylacetonatobis(ethylene)rhodium(I) (0.3 mmol),(S)-(−)-2,2′-Bis(diphenyl-phosphino)-1,1′-binaphthalene (0.045 mmol),4-(trifluoromethyl)phenylboronic acid (2 mmol), K₂CO₃ (0.5 mmol), andbut-2-enoic acid amide (1 mmol) are added into a 25-mL round-bottomedflask containing a magnetic stirrer bar, a septum inlet, and a refluxcondenser. The flask is flashed with argon and then charged with1,4-dioxane (3 mL) and de-ionized H₂O (0.5 mL). The reaction mixture isstirred for 16 hours at 100° C. The(R)-3-(4-trifluoromethylphenyl)butyramide is extracted with ethylacetate, washed with brine, and dried over anhydrous magnesium sulfate.Chromatography over silica gel gives the desired product.

Example 21 Preparation of Compound AA[3-(4-Trifluoromethylphenyl)-pentanamide]

To a chilled (0° C.) solution of lithium bis(trimethylsilyl)amide (1.0M, 50 mL) was dropwise added a solution of trimethylphosphonoacetate,keeping the temperature below 10° C. The solution was then allowed towarm to room temperature and stirred for an additional five minutes,after which a solution of 4′-(trifluoromethyl)propiophenone in THF (25mL) was added in one portion. The solution was slowly heated to 50° C.for eight hours. The solution was cooled to room temperature, thendiluted with a 10% NH₄Cl solution (100 mL), and extracted with ethylacetate (2×100 mL). The organic layers were combined and dried overMgSO₄, filtered, and the filtrate concentrated to a white solid whichwas recrystallized from hexane/ethyl acetate to give 5.42 grams of3-(4-trifluoromethylphenyl)pent-2-enoic acid methyl ester intermediate(85% yield).

To a solution of 3-(4-trifluoromethylphenyl)pent-2-enoic acid methylester in THF/MeOH was added a solution of sodium hydroxide in H₂O (15mL). The resulting solution was stirred at room temperature for 12hours, and acetic acid (3 grams) was added. The solution was thenconcentrated to an oil. The oil was dissolved in ethyl acetate (100 mL)and washed with H₂O (3×100 mL). The ethyl acetate extracts were combinedand dried over MgSO₄, filtered, and concentrated to a semi-solid whichwas then dissolved in MeOH/THF (2:1, 50 mL) and shaken with 10% Pd/Cunder 50 psi of hydrogen pressure for 24 hours. TLC showed that thereaction was incomplete. Additional 10% Pd/C was added (500 mg) and thesuspension was shaken for an additional 24 hours. The suspension wasthen filtered and the filtrate concentrated to a semi-solid (4.97 g).The solid was dissolved in CH₂Cl₂ (30 mL) and the resulting solutioncooled to 0° C. To this solution was added oxalyl chloride followed byone drop of DMF from a 9-inch disposable pipette. The solution wasstirred for 8 hours and then concentrated to a solid which was dissolvedin additional CH₂Cl₂ (30 mL). The solution was again concentrated to asemi-solid which was dissolved in additional CH₂Cl₂ (50 mL), and theresulting solution added dropwise to a chilled (5° C.) and mechanicallystirred solution of NH₄OH (10 mL) over approximately five minutes. Thesuspension was then concentrated to a gummy/aqueous mixture which wasextracted with ethyl acetate (2×100 mL). The ethyl acetate extracts werecombined and dried over MgSO₄, filtered, and the filtrate concentratedto a crude amber-solid which was adsorbed onto silica gel (50 g) usingCH₂Cl₂/THF. The solid was then chromatographed on silica gel(EtOAc/hexane) to give 2.25 grams of off-white solid (37% yield). Thismaterial was determined to be 100% pure by LC/MS. ¹H-NMR gave signalsconsistent with the product's structure and indicated greater than 98%purity.

Example 22 Preparation of Compound AW [3-(4-Isopropylphenyl)butyramide]

To a chilled (0° C.) solution of lithium bis(trimethylsilyl)amide (1.0M, 56 mL) was dropwise added a solution of trimethylphosphonoacetate,keeping the temperature below 10° C. The solution was then allowed towarm to room temperature and stirred for an additional five minutesafter which a solution of p-isobutylacetophenone in THF (25 mL) wasadded in one portion. The solution was slowly heated to 65° C. andallowed to reflux for thirty hours. The solution was cooled to roomtemperature then diluted with a 10% NH₄Cl solution (100 mL), andextracted with ethyl acetate (2×100 mL). The organic layers werecombined and dried over MgSO₄, filtered, and filtrate concentrated to awhite solid which was recrystallized from hexane/ethyl acetate to give5.93 grams of 3-(4-isobutylphenyl)but-2-enoic acid methyl esterintermediate (89.9% yield).

To a solution of 3-(4-isobutylphenyl)but-2-enoic acid methyl ester inTHF/MeOH was added a solution of sodium hydroxide in H₂O (15 mL). Theresulting solution was stirred at room temperature for 12 hours andacetic acid (3 grams) was added. The solution was then concentrated toan oil. The oil was dissolved in ethyl acetate (150 mL) and washed withH₂O (3×100 mL). The ethyl acetate extracts were combined and dried overMgSO₄, filtered, and concentrated to a solid (4.98 g) which was thendissolved in MeOH/THF (2:1, 50 mL) and shaken with 10% Pd/C under 50 psiof hydrogen pressure for 24 hours. TLC showed that the reaction wasincomplete. Additional 10% Pd/C was added (500 mg) and the suspensionwas shaken for an additional 24 hours. The suspension was then filteredand the filtrate concentrated to a solid (4.75 g). The solid wasdissolved in CH₂Cl₂ (30 mL) and the resulting solution cooled to 0° C.To this solution was added oxalyl chloride followed by one drop of DMFfrom a 9-inch disposable pipette. The solution was stirred for six hoursand then concentrated to a solid which was dissolved in additionalCH₂Cl₂ (30 mL). The solution was again concentrated to a semi-solidwhich was dissolved in additional CH₂Cl₂ (50 mL), and the resultingsolution added dropwise to a chilled (5° C.) and mechanically stirredsolution of NH₄OH (10 mL) over approximately five minutes. Thesuspension was then concentrated to a solid/aqueous mixture which wasextracted with ethyl acetate (2×100 mL). The ethyl acetate extracts werecombined and dried over MgSO₄, filtered, and the filtrate concentratedto a crude solid which was adsorbed onto silica gel (50 g) usingCH₂Cl₂/THF. The solid was then chromatographed on silica gel(EtOAc/Hexane) to give 2.5 grams of off-white solid (40% yield). Thismaterial was determined to be 100% pure by LC/MS. ¹H-NMR gave signalsconsistent with the product's structure and indicated greater than 98%purity.

Example 23 Preparation of Compound AE[3-(6-Methoxynaphthalen-2-yl)-butyramide]

To a chilled (0° C.) solution of lithium bis(trimethylsilyl)amide (1.0M, 50 mL) was dropwise added a solution of trimethylphosphonoacetate,keeping the temperature below 10° C. The solution was then allowed towarm to room temperature and stirred for an additional ten minutes afterwhich a solution of 2-acetyl-6-methoxynaphthalene in THF (20 mL) wasadded in one portion. The solution was slowly heated to 50° C. forfourteen hours. The solution was cooled to room temperature then dilutedwith a 10% NH₄Cl solution (100 mL), and extracted with ethyl acetate(2×100 mL). The organic layers were combined and dried over MgSO₄,filtered, and filtrate concentrated to a white solid which wasrecrystallized from hexane/ethyl acetate to give 5.88 grams of3-(6-methoxynaphthalen-2-yl)but-2-enoic acid methyl ester intermediate(92% yield).

To a solution of 3-(6-methoxynaphthalen-2-yl)but-2-enoic acid methylester in THF/MeOH was added a solution of sodium hydroxide in H₂O (15mL). The resulting solution was stirred at room temperature for 12 hoursand acetic acid (3 grams) was added. The solution was then concentratedto a solid residue. The solid was dissolved in ethyl acetate (150 mL)and washed with H₂O (3×100 mL). The ethyl acetate extracts were combinedand dried over MgSO₄, filtered, and concentrated to a solid which wasthen dissolved in MeOH/THF (2:1, 50 mL) and shaken with 10% Pd/C under50 psi of hydrogen pressure for 24 hours. TLC showed that the reactionwas incomplete. Additional 10% Pd/C was added (500 mg) and thesuspension was shaken for an additional 24 hours. The suspension wasthen filtered and the filtrate concentrated to a semi-solid (4.97 g).The solid was dissolved in CH₂Cl₂ (30 mL) and the resulting solutioncooled to 0° C. To this solution was added oxalyl chloride followed byone drop of DMF from a 9-inch disposable pipette. The solution wasstirred for six hours and then concentrated to a solid which wasdissolved in additional CH₂Cl₂ (30 mL). The solution was againconcentrated to a semi-solid which was dissolved in additional CH₂Cl₂(50 mL), and the resulting solution added dropwise to a chilled (5° C.)and mechanically stirred solution of NH₄OH (10 mL) over approximatelyfifteen minutes. The suspension was then concentrated to a gummy/aqueousmixture which was extracted with ethyl acetate (2×100 mL). The ethylacetate extracts were combined and dried over MgSO₄, filtered, and thefiltrate concentrated to a crude solid which was adsorbed onto silicagel (50 g) using CH₂Cl₂/THF. The solid was then chromatographed onsilica gel (EtOAc/hexane) to give 1.87 grams of off-white solid (32%yield). This material was determined to be 100% pure by LC/MS. ¹H-NMRgave signals consistent with the product's structure and indicatedgreater than 98% purity.

Example 24 Preparation of Compound AX[3-(2-Fluoro-biphenyl-4-yl)butyramide]

To a chilled (0° C.) solution of 2-(2-fluoro-biphenyl-4-yl)propionicacid in THF was added isobutyl chloroformate followed by dropwiseaddition of TEA. The resulting white slurry was allowed to stir for 1hour and then diluted with THF (50 mL) and filtered. The filter cake waswashed with additional THF (50 mL) and the filtrate was concentrated toapproximately 50 mL using a rotary evaporator. The concentrated filtratewas then stirred at −20° C. and a solution of NaBH₄ in H₂O (20 mL) wasdropwise added over a period of 15 minutes. The resulting suspension wasstirred for 2 hours at 0° C., diluted with water (200 mL), and extractedwith ethyl acetate (2×100 mL). The ethyl acetate layers were combinedand washed with 1.0 N HCl solution (100 mL) followed by a 5% bicarbonatesolution wash (100 mL). The ethyl acetate solution was then concentratedto an oily residue of 2-(2-fluoro-biphenyl-4-yl)propanol (4.47 g, 95%yield).

To a chilled (0° C.) solution of 2-(2-fluoro-biphenyl-4-yl)propanol inCH₂Cl₂ was added methanesulfonyl chloride followed by dropwise additionof TEA. The resulting white slurry was allowed to stir for 1 hour andthen diluted with H₂O (200 mL). The suspension was extracted with CH₂Cl₂(2×100 mL). The CH₂Cl₂ layers were combined and with water (2×100 mL)and a 5% NH₄OH solution (100 mL). The CH₂Cl₂ layer was then washed withadditional H₂O (200 mL) and dried over MgSO₄. The CH₂Cl₂ layer wasconcentrated to an oily residue which was dissolved in anhydrous DMF (50mL). This solution was treated with NaCN and stirred at 60° C. for 14hours. The TLC indicated one major less polar eluting product (relativeto mesylate) and several minor less polar eluting products relative toboth the major and mesylate products. The reaction was cooled to roomtemperature and diluted with H₂O (100 mL). The solution was extractedwith ethyl acetate (2×100 mL), dried over MgSO₄, and concentrated to anoily residue which was chromatographed on silica gel (90% Hex, 10%EtOAc) to give 3-(2-fluoro-biphenyl-4-yl)butyronitrile as an oil whichslowly solidified on standing at room temperature (2.05 g, 49% yield).

To a solution of 3-(2-fluoro-biphenyl-4-yl)butyronitrile in tert-butylalcohol was added 1.87 g of finely powdered potassium hydroxide. Theresulting suspension was stirred and heated to 70° C. for 2.5 hours andcooled to room temperature. The reaction suspension was diluted with 1.0N HCl solution (100 mL) and extracted with ethyl acetate (2×100 mL). Theethyl acetate extracts were combined and washed with 5% bicarbonatesolution (100 mL) and then with H₂O (100 mL). The organics were thendried over MgSO₄, and concentrated to a white solid which wasre-crystallized several times with EtOAc/Hex to give white flaky prisms(1.62 g, 75% yield).

Example 25 Preparation of Compound AY[3-(4-Morpholin-4-yl-phenyl)-butyramide]

To a chilled (0° C.) solution of potassium tert-butoxide (1.0 M, 37.1mL) was dropwise added a solution of trimethylphosphonoacetate, keepingthe temperature below 25° C. The solution was then allowed to warm toroom temperature and stirred for an additional five minutes, after whicha solution of 4-morpholinoacetophenone in THF (20 mL) was added in oneportion. The solution was slowly heated to 60° C. for 36 hours. Thesolution was cooled to room temperature, then diluted with a 1.0N HClsolution (100 mL), and extracted with ethyl acetate (2×100 mL). Theorganic layers were combined and dried over MgSO₄, filtered, and thefiltrate concentrated to a white solid which was recrystallized fromhexane/ethyl acetate to give 3.33 grams of3-(4-morpholinophenyl)but-2-enoic acid methyl ester intermediate (69.9%yield).

To a solution of 3-(4-morpholinophenyl)but-2-enoic acid methyl ester inTHF/MeOH (1:1) was added a solution of sodium hydroxide in H₂O (15 mL).The resulting solution was stirred at room temperature for 15 hours andacetic acid (3 grams) was added. The pH of the solution was measured at6.5. The solution was then concentrated to an oil. The oil was dissolvedin ethyl acetate (150 mL) and washed with H₂O (3×100 mL). The ethylacetate extracts were combined and dried over MgSO₄, filtered, andconcentrated to an amorphous solid which was then dissolved in MeOH (50mL) and shaken with 10% Pd/C under 50 psi of hydrogen pressure for 8hours. TLC showed that the reaction was complete. The suspension wasthen filtered and the filtrate concentrated to a semi-solid (2.77 g).The semi-solid was dissolved in CH₂Cl₂ (30 mL) and the resultingsolution cooled to 0° C. To this solution was added oxalyl chloridefollowed by one drop of DMF from a 9-inch disposable pipette. Thesolution was stirred for four hours and then concentrated to a solidwhich was dissolved in additional CH₂Cl₂ (30 mL). The solution was againconcentrated to a semi-solid which was dissolved in additional CH₂Cl₂(50 mL), and the resulting solution added dropwise to a chilled (5° C.)and mechanically stirred solution of NH₄OH (15 mL) over approximatelyfive minutes. The solution was then concentrated to a solid/aqueousmixture which was extracted with ethyl acetate (2×100 mL). The ethylacetate extracts were combined and dried over MgSO₄, filtered, and thefiltrate concentrated to a crude solid which was adsorbed onto silicagel (50 g) using CH₂Cl₂/THF. The solid was then chromatographed onsilica gel (EtOAc/hexane) to give 2.1 grams of beige plates (46% yield).This material was determined to be 100% pure by LC/MS. ¹H-NMR gavesignals consistent with the product's structure and indicated greaterthan 98% purity.

Example 26 Preparation of Compound Q-1[(1R,2R)-2-Phenylcyclopropane-carboxylicacid-((S)-1-carbamoyl-propyl)amide]

A solution of trans-2-phenyl-cyclopropanecarbonylchloride in CH₂Cl₂ (20mL) was added dropwise into a solution of L-2-aminobutanamidehydrochloride (1.61 g, 11.6 mmol) and triethylamine (3.36 g, 33.2 mmol)in CH₂Cl₂ (60 ml) at zero degree Celsius. The reaction mixture stirredat room temperature under nitrogen overnight.

The reaction mixture was evaporated under reduced pressure and resultingresidue re-dissolved in ethyl acetate/water mixture. The mixture wastransferred into a separatory funnel using H₂O (50 mL) and ethyl acetate(80 mL). The mixture was equilibrated and the aqueous phase was removed.The organic layer was washed with 1.0M HCl (20 mL), H₂O (90 mL) andbrine (120 mL) consecutively. The organic layer was dried over anhydrousmagnesium sulfate, filtered, and excess solvent was removed underreduced pressure. The resulting orange-brown solid was purified using aBiotage SP4 System (Column Si 40+M 90:10, CH₂Cl₂/MeOH), which afforded0.365 g of white powder (24% yield). This material was determined to be100% pure by GC/MS. ¹H-NMR gave signals consistent with the product'sstructure and indicated greater than 98% purity.

FIGS. 4A-4O illustrate additional examples of the syntheses of variouscompounds and key intermediates (Schemes 1-15), drawn from theliterature of synthetic organic chemistry, from which skilled artisanswill be able to envision the preparation of various additional compoundsof the present invention.

Example 27 Demonstration of Biological Activity in Rodent AnticonvulsantModels of Epilepsy

The anticonvulsant activities of various compounds of the invention weredemonstrated in vivo in various rodent (mouse and rat) models ofepilepsy. The animal testing was performed as described in White et al.,“Discovery and preclinical development of antiepileptic drugs,” inAntiepileptic Drugs, 5^(th) ed., Levy et al. (Eds.), Lippincott Williamsand Wilkins, Philadelphia, Pa., 2002 (968 pp.), pp. 36-48, andreferences contained therein, which are hereby incorporated herein intheir entirety. The results for compounds A, G, H, I, and F aresummarized below in Tables 2 and 3.

TABLE 2 ANTICONVULSANT PROFILES OF COMPOUNDS OF THE PRESENT INVENTION,FOLLOWING I.P. ADMINISTRATION TO MICE MID₅₀ or ED₅₀ (mg/kg) and (PI)*Compound MID₅₀ MES^(a) (PI) s.c. MET^(b) (PI) AGS^(c) (PI) 6 Hz (PI) A<100 <100 ≦100 — >30 (<3.3) G <100 <100 ≦100 — — I <100 <100 ≦100 — — H158.98 76.11 (2.1) 91.36 (1.74)  22.5 (7.1) 54.98 (2.9) F 208.37 85.32(2.4) 85.47 (2.4)  41.30 (5) 80.8 (2.6) MID₅₀ = median minimal motorimpairment dose; ED₅₀ = median effective dose; ^(a)Maximal ElectroshockSeizure test. ^(b)Subcutaneous Metrazol Seizure threshold.^(c)Audiogenic Seizure susceptible. (PI)* = Protective Index =MID₅₀/ED₅₀.

TABLE 3 MINIMAL MOTOR IMPAIRMENT AND PROFILES OF ANTICONVULSANT ACTIVITYOF COMPOUNDS OF THE PRESENT INVENTION IN RATS s.c. MET Compound MID₅₀(mg/kg) MES (mg/kg) (PI) (mg/kg) (PI) A 244.90 28.80 (8.5) 45.00 (5.4) H >500 56.73 (>9)  88.09 (>5.7) F >500 (none observed)  26.39 (>19) >250

Example 28 Demonstration of Biological Activity in Rat AnticonvulsantModels of Status Epilepticus

The anticonvulsant activities of various compounds of the presentinvention were also demonstrated in vivo in two rat models of statusepilepticus. The animal testing was performed using the protocolsdeveloped in the Anticonvulsant Screening Program (ASP) at the NationalInstitute of Neurological Disorders and Stroke (NINDS), NationalInstitutes of Health (NIH). The results are summarized below in Table 4.

TABLE 4 Compound Activities in Status Epilepticus Models (ASP/NINDS/NIHdata) (Pilocarpine-induced Status Epilepticus in Rats) Counter-MeasuresScreening: Test 71 = “Prevention of Pilocarpine-induced StatusEpilepticus, in Rats” Test 72 = “Pilocarpine-induced StatusEpilepticus - Acute Intervention, in Rats” Test (Prevention) (AcuteIntervention) Compound Test 71 (time 0) Test 72 (30 min.) A^(a)  65mg/kg 120 mg/kg B 300 mg/kg — D 200 mg/kg 400 mg/kg O 450 mg/kg InactiveL 450 mg/kg — M 600 mg/kg Inactive K 300 mg/kg 600 mg/kg I^(a)  65 mg/kg130 mg/kg H^(a) 200 mg/kg 176 mg/kg G^(a) 200 mg/kg 200 mg/kg F^(a)  65mg/kg — J 600 mg/kg — AW^(a) <450 mg/kg  — ^(a)Weight gain or weightmaintenance in rats.

Example 29 Demonstration of Lack of Toxicity in In Vitro (LDH and CellProliferation) Assays

Compounds A, I, H, and F were tested by Stem Cell Innovations, Inc.(Houston, Tex.) in their ACTIVTox® Human Liver Cell-based assays (usingC3A hepatocyte cells). Specifically, the compounds were tested in theLDH release assay, which determines the release of Lactate DeHydrogenase(an indicator of cell death) at various concentrations of test compound.

A concentration of 100 μM of test compound is a much higher level ofexposure to liver cells than would ever be expected under physiologicalconditions. Therefore, using 100 μM as a standard test concentration(for comparative purposes), the ratio of the absorbance (which measuresthe level of LDH release) resulting from the presence of the testcompound versus the negative control is a value known as the “average(or mean) fold control” (Average Fold Control=Average ofAbsorbance/Average of Negative Control). An average fold control valuebelow 1.75 indicates that the test compound has no cyto- or hepatotoxicactivity in the LDH release assay.

The ACTIVTox data (see Table 5, below) show that the compounds A, I, Hand F are not cyto- or hepatotoxic at physiologically relevantconcentrations (i.e., <100 μM).

TABLE 5 Cytotoxic and hepatotoxic data (mean fold control at 100 μM)from the ACTIVTox LDH release assay. LDH release, mean Test Compoundfold control (at 100 μM) A 1.05 I 1.03 H 1.32 F 1.47Compounds A and I were also tested in the ACTIVTox Cell ProliferationAssay and were found to be non-toxic to proliferating cells at aconcentration of 100 μM, with mean fold control values of 1.15 and 1.25,respectively.

The present invention may be embodied in other specific forms withoutdeparting from its spirit or essential characteristics. The describedembodiments are to be considered in all respects only as illustrativeand not restrictive. The scope of the invention is, therefore, indicatedby the appended claims rather than by the foregoing description. Allchanges which come within the meaning and range of equivalency of theclaims are to be embraced within their scope. All references recitedherein are incorporated herein in their entirety by specific reference.

1. A CNS-active compound having Formula I:

wherein Ar is an optionally substituted phenyl, optionally substitutednaphthyl, optionally substituted tetrahydronaphthyl, optionallysubstituted indane, or an optionally substituted heterocyclic aryl,wherein up to 5 substituents are optionally present on Ar and eachsubstituent is independently selected from the group consisting ofhydrogen, alkyl, cycloalkyl, halogen, alkoxy, thioalkyl, sulfoxyalkyl,sulfonylalkyl, alkylene dioxy, haloalkyl, haloalkoxy, OH, CH₂OH, CONH₂,CN, acetoxy, N(alkyl)₂, benzyl, benzyloxy, α,α-dimethylbenzyl, NO₂, CHO,CH₃CH(OH), acetyl, OCH₂COOH, and an optionally substituted aromatic ringsystem; said optionally substituted aromatic ring system being selectedfrom the group consisting of phenyl, phenoxy, and heterocyclic aryl,wherein up to 5 substituents are optionally present on the aromatic ringsystem, and each substituent is independently selected from the groupconsisting of: hydrogen, alkyl, cycloalkyl, halogen, alkoxy, thioalkyl,sulfoxyalkyl, sulfonylalkyl, alkylene dioxy, haloalkyl, haloalkoxy, OH,CH₂OH, CONH₂, CN, acetoxy, N(alkyl)₂, NO₂, CHO, CH₃CH(OH), acetyl, andOCH₂COOH; R₁ and R₂ are each independently H, optionally substitutedalkyl, optionally substituted cycloalkyl, or optionally substitutedCW₂phenyl, wherein each W is independently selected from the groupconsisting of H, methyl and ethyl with the proviso that Ws are notethyl, and wherein up to 5 substituents are optionally present in thephenyl group or cycloalkyl, and each substituent is independentlyselected from the group consisting of halogen, alkoxy, thioalkyl,sulfoxyalkyl, sulfonylalkyl, haloalkyl, haloalkoxy, CONH₂, CN, acetoxy,N(alkyl)₂, NO₂, and acetyl; when one of R₁ or R₂ is H then the other ofR₁ or R₂ is (CH₂)₂SO₃H, or CHZCOOH, wherein Z is one of the groupconsisting of H, CH₃, CH(CH₃)₂, CH₂C₆H₅, CH₂CH(CH₃)₂, and CH(CH₃)CH₂CH₃;or R₁ and R₂ together are a cycloalkyl; R₃ is one of a hydroxy, alkyl,cycloalkyl, or together with R₄ a cycloalkyl with the proviso that whenone of R₃ or R₄ is OH then the other of R₃ or R₄ is not an ethyl; R₄ isone of an alkyl, cycloalkyl, or together with R₃ cycloalkyl; and X isone of nothing, methylene, ketone, CHOH, oxygen, NR₁, sulfur, sulfone,or sulfoxide.
 2. A CNS-active compound having Formula II:

wherein R₁ and R₂ are each independently at least one of H, alkyl,cycloalkyl, or CW₂phenyl, wherein each W is independently selected fromthe group consisting of H, methyl and ethyl with the proviso that bothWs are not ethyl, and wherein up to 5 substituents may be present in thephenyl or cycloalkyl groups, and each substituent is independentlyselected from the group consisting of halogen, alkoxy, thioalkyl,sulfoxyalkyl, sulfonylalkyl, haloalkyl, haloalkoxy, CONH₂, CN, acetoxy,N(alkyl)₂, NO₂, and acetyl; when one of R₁ or R₂ is H then the other ofR₁ or R₂ is (CH₂)₂SO₃H, or CHZCOOH, wherein Z is one of the groupconsisting of H, CH₃, CH(CH₃)₂, CH₂C₆H₅, CH₂CH(CH₃)₂, and CH(CH₃)CH₂CH₃;or R₁ and R₂ together are a cycloalkyl; R₄ and R₅ are each independentlyan optionally substituted phenyl or optionally substituted heterocyclicaryl, wherein up to 5 substituents may be present and each substituentis independently selected from the group consisting of halogen, alkoxy,thioalkyl, sulfoxyalkyl, sulfonylalkyl, haloalkyl, haloalkoxy, CH₂OH,CONH₂, CN, acetoxy, N(alkyl)₂, NO₂, acetyl, and OCH₂COOH; and Y iseither nothing or methylene.
 3. A CNS-active compound having one of theFormulas 1-9:

wherein R₁ is one of H, CH₃, C₂H₅, (CH₂)₂SO₃H, or CHZCOOH; Z is one ofH, CH₃, CH(CH₃)₂, CH₂C₆H₅, CH₂CH(CH₃)₂, or CH(CH₃)CH₂CH₃; R₂ and R₃ areindependently one of H or CH₃; R₄ is one of H, CH₃, OH, or OCH₃; R₅ isone of H, Cl, F, CF₃, CN, C1-C5 alkyl, C1-C5 alkoxy, OCF₃ or CONR₁, R₂;n=1-5; Q=O, NR₂, C═O, S, SO, or SO₂; and X═O, NR₂, nothing, C═O, S, SO,or SO₂.
 4. A CNS-active compound having one of Formulas A-BA:


5. A pharmaceutical composition for modulating CNS activity, thecomposition comprising: a pharmaceutically-acceptable carrier; and aCNS-active compound of one of claims 1-4 combined with the carrier.
 6. Apharmaceutical composition as in claim 5, further comprising anexcipient.
 7. A pharmaceutical composition as in claim 5, wherein theCNS-active compound is present in a therapeutically effective amount tomodulate CNS activity.
 8. A pharmaceutical composition as in claim 7,wherein the therapeutically effective amount is sufficient for at leastone of the following: to provide anticonvulsant activity to a subject;to treat and/or prevent convulsions in a subject; to treat and/orprevent seizures in a subject; to treat and/or prevent spasticity in asubject; to treat and/or prevent affective mood disorders in a subject;to treat and/or prevent bipolar mood disorder in a subject; to treatand/or prevent chronic headaches in a subject; to treat and/or preventcluster headaches in a subject; to treat and/or prevent migraineheadaches in a subject; to treat and/or prevent restlessness syndromesin a subject; to treat and/or prevent neuropathic pain in a subject; orto treat and/or prevent movement disorders in a subject.
 9. A method formodulating CNS activity, the method comprising: administering aCNS-active compound of one of claims 1-4 to a subject.
 10. A method asin claim 9, wherein the CNS-active compound is combined with apharmaceutically-acceptable carrier.
 11. A method as in claim 9, whereinthe CNS-active compound is administered to the subject in atherapeutically effective amount to modulate CNS activity in thesubject.
 12. A method as in claim 11, wherein the therapeuticallyeffective amount is sufficient for at least one of the following: toprovide anticonvulsant activity to a subject; to treat and/or preventconvulsions in a subject; to treat and/or prevent seizures in a subject;to treat and/or prevent spasticity in a subject; to treat and/or preventaffective mood disorders in a subject; to treat and/or prevent bipolarmood disorder in a subject; to treat and/or prevent chronic headaches ina subject; to treat and/or prevent cluster headaches in a subject; totreat and/or prevent migraine headaches in a subject; to treat and/orprevent restlessness syndromes in a subject; to treat and/or preventneuropathic pain in a subject; or to treat and/or prevent movementdisorders in a subject.
 13. A method as in claim 11, wherein thetherapeutically effective amount is sufficient to treat and/or preventthe symptoms of at least one of anxiety, depression, insomnia, migraineheadaches, schizophrenia, Parkinson's disease, spasticity, Alzheimer'sdisease, bipolar disorder, chronic or neuropathic pain, stroke, chronicneurodegenerative diseases, Huntington's disease, traumatic braininjury, spinal cord injury, or status epilepticus.
 14. A method as inclaim 11, wherein the therapeutically effective amount is sufficient fora chemical countermeasure.
 15. A method of manufacturing a CNS-activecompound [3-(4-cyanophenoxy)butyramide], the method comprising:


16. A method as in claim 15, further comprising: heating 4-cyanophenolin a basic solution at reflux; adding β-butyrolactone to the refluxingsolution; cooling the solution to room temperature; preparing a biphasicmixture of the solution by adding water and diethyl ether; removing adiethyl ether layer after formation; acidifying the aqueous layer afterformation by adding a HCl solution at about pH ˜2; extracting theacidified aqueous layer with ethyl acetate; drying the ethyl acetatelayer to yield 3-(4-cyanophenoxy)butyric acid]; preparing a solution of3-(4-cyanophenoxy)butyric acid in an organic solvent; treating thesolution with oxalyl chloride to obtain [3-(4-cyanophenoxy)butyrylchloride]; bubbling ammonia gas through the solution of3-(4-cyanophenoxy)butyryl chloride; and obtaining[3-(4-cyanophenoxy)butyramide] from the solution.